The pharmacological limitations of peptides, such as their poor bioavailability or short elimination half-life, are the main reasons for the interest in a rational design of non-peptide mimetics of bioactive peptides. A large variety of modifications of peptide structures have been used for conformationally directed drug design to investigate the active peptide-receptor binding conformation. Of these, constrained peptidomimetics and cyclization of peptides remains of special interest to obtain a distinct bioactive conformation.
Carbohydrates present an attractive option for non-peptide scaffolding. Furanoid sugar amino acids have been used as dipeptide isosteres. They induce turn structures when incorporated in small linear peptides (Chakraborty, T. K. etal; J. Org. Chem. 2000, 65, 6441–6457).
The peptide sequence Leu-Met-Tyr-Pro-Thr-Tyr-Leu-Lys (SEQ ID NO: 1) is reported to be the receptor binding inhibitor of vasoactive intestinal peptide (Said, S. I. & Mutt, V., Ann. N. Y. Acad. Sci., 1, 527,1988). The role of this octapeptide as VIP receptor binding inhibitor has been described in the U.S. Pat. No. 5,217,953. In our U.S. Pat. No. 6,156,725 we have described the anti-cancer role of this VIP receptor binding inhibitor in combination with other neuropeptide analogs. In U.S. patent application Ser. No. 09/248,382, now abandoned, we have described novel analogs of this VIP receptor binding inhibitor incorporating α,α.-dialkylated amino acids and in another U.S. patent application Ser. No. 09/630,345, now U.S. Patent 6,828,304, we have described the lipoconjugates of this octapeptide.
In the present invention we have made peptidomimetic analogs of the mentioned VIP receptor binding inhibitor (SEQ ID NO: 1) replacing the di-/tri-peptides having proline as one of the amino acids, or proline alone, with furanoid sugar amino acids.
Throughout the application the following abbreviations are used with the following meanings:
PyBOP:-Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexofluorophospate
DMF: Dimethyl formamide
HBTU:-O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexofluoro-phosphate
HOBt:-1-Hydroxy Benzotriazole
DCC:-Dicyclohexyl carbodiimide
DIPCDI:-Diisopropyl carbodiimide
DMAP (4-dimethylamino pyridine)
DIEA:-Diisopropyl ethylamine
DMF:-Dimethyl formamide
DCM:-Dichloromethane
NMP:-N-Methyl-2-pyrrolidinone
TFA: Trifluoroacetic acid
PDC: Pyridinium dichromate
Boc: t-Butyloxy carbonyl
Fmoc: Fluorenyl methoxy carbonyl
Throughout the specification and claims, the amino acids residues are designated by their standard abbreviations. Amino acids denote L-configuration unless otherwise indicated by D appearing before the symbol and separated from it by hyphen.